Regulation of tumor promotion by RasGRP1
Principal Investigator: JOE WILLIAM RAMOS
Abstract: DESCRIPTION (provided by applicant): The mouse model of skin carcinogenesis has served to investigate the multistage nature of tumorigenesis and to identify novel oncogenes and tumor suppressor genes, as well as signaling pathways relevant in cancer. In the classic two-stage carcinogenesis model, Ras is activated by mutations induced by a carcinogen, and subsequent treatment with phorbol esters induces tumor promotion. However, the mechanisms that lead to tumor formation of cells initiated by Ras -and the participation of phorbol ester signaling pathways- are still poorly understood. Using the mouse skin model, we have identified RasGRP1 as a novel regulator of skin carcinogenesis. RasGRP1 links phorbol esters and Ras, since it is both, a high affinity phorbol ester receptor and a Ras activator. Using genetically modified mice we have shown that RasGRP1 participates in tumor initiation and progression in the two-stage carcinogenesis model through the biochemical activation of wild type Ras. Additionally, transgenic mice overexpressing RasGRP1 in the epidermis are prone to develop skin tumors spontaneously. Taken together, we hypothesize that RasGRP1 participates in carcinogenesis by mediating biochemical Ras activation and cooperating with oncogenic Ras in tumor formation. In this application, we propose to identify the mechanisms of cooperation between Ras and RasGRP1 during skin carcinogenesis, both in the absence and presence of Ras oncogenic mutations. In addition, we plan to extend our observation in mouse models to a human model using the 3-D organotypic culture of human skin. The specific aims are: (1) Determine the mechanism of tumorigenesis induced by RasGRP1 in the absence of Ras oncogenic mutations: following findings from our recent studies on wounding-induced tumors in the RasGRP1 transgenic mice, we will focus on the potential role of cytokines and EGFR ligands in activation of the RasGRP1-Ras axis in the skin;(2) Investigate the cooperation between RasGRP1 and oncogenic Ras in tumor progression in the skin: our hypothesis is that RasGRP1 activates wild type Ras isoforms, particularly N-Ras, and cooperates with oncogenic Ras in tumor progression;and (3) Elucidate the role of RasGRP1 in human keratinocyte homeostasis and transformation: we will use human in vitro models to validate and understand the functions of RasGRP1 in carcinogenesis. The significance of the studies is that the identification of RasGRP1 as a relevant target in Ras modulation in carcinogenesis can be used to develop new interventions for chemoprevention and/or cancer therapy. Moreover, the findings derived from this proposal should also contribute to advance our understanding of Ras signaling pathways beyond skin carcinogenesis, and may have applications to other systems where RasGRP1 is also expressed.
Funding Period: 2002-08-01 - 2016-04-30
more information: NIH RePORT
- Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytesMatthew C Tuthill
Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Room 315, 1236 Lauhala Street, Honolulu, HI 96813, USA
Mol Cancer Ther 5:602-10. 2006..This result may have implications in the understanding of the antitumor effects of bryostatin 1 in the skin...
- Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skinCarolyn E Oki-Idouchi
Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, HI 96813, USA
Cancer Res 67:276-80. 2007..Taken together, these data are the first to provide evidence of a novel role for RasGRP1 in skin carcinogenesis and suggest that RasGRP1 may participate in tumorigenesis through modulation of Ras and autocrine pathways...
- RasGRP1 overexpression in the epidermis of transgenic mice contributes to tumor progression during multistage skin carcinogenesisCourtney T Luke
Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, HI 96813, USA
Cancer Res 67:10190-7. 2007..The present data suggests that RasGRP1 participates in skin carcinogenesis via biochemical activation of endogenous wild-type Ras and predisposes to malignant progression in cooperation with Ras oncogenic signals...
- RasGRP1 transgenic mice develop cutaneous squamous cell carcinomas in response to skin wounding: potential role of granulocyte colony-stimulating factorFederico R Diez
Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA
Am J Pathol 175:392-9. 2009....
- RasGRP1 is essential for ras activation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in epidermal keratinocytesAmrish Sharma
Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA
J Biol Chem 285:15724-30. 2010..Given the role of TPA as a skin tumor promoter, our findings provide additional support for a role for RasGRP1 in skin carcinogenesis...
- Targeted deletion of RasGRP1 impairs skin tumorigenesisAmrish Sharma
Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA
Carcinogenesis 35:1084-91. 2014..Thus, we propose that RasGRP1 upregulates signaling from Ras and contributes to epidermal tumorigenesis by increasing the total dosage of active Ras. ..
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